REVIEW

X-linked ichthyosis: An oculocutaneous

genodermatosis
Neil F. Fernandes, MD,a Camila K. Janniger, MD,a,b and Robert A. Schwartz, MD, MPHa,b,c
Newark, New Jersey

X-linked ichthyosis (XLI) is an X-linked recessive disorder of cutaneous keratinization with possible
extracutaneous manifestations. It was first described as a distinct type of ichthyosis in 1965. XLI is caused by
a deficiency in steroid sulfatase activity, which results in abnormal desquamation and a retention
hyperkeratosis. XLI is usually evident during the first few weeks of life as polygonal, loosely adherent
translucent scales in a generalized distribution that desquamate widely. These are quickly replaced by
large, dark brown, tightly adherent scales occurring primarily symmetrically on the extensor surfaces and
the side of the trunk. In addition, extracutaneous manifestations such as corneal opacities, cryptorchidism,
and abnormalities related to contiguous gene syndromes may be observed. Diagnosis of XLI is usually
made clinically, as the histopathology is nonspecific, but confirmation may be obtained through either
biochemical or genetic analysis. Treatment should focus on cutaneous hydration, lubrication, and
keratolysis and includes topical moisturizers and topical retinoids ( J Am Acad Dermatol 2010;62:480-5.)

Key words: genodermatosis; hyperkeratosis; ichthyosis; X-linked.

males.5 XLI has rarely been described in homozy-

T he term ‘‘ichthyosis’’ refers to a group of

hereditary and acquired cutaneous disorders
of keratinization. ‘‘Ichthyosis’’ is derived from
the Greek root ‘‘ichthys,’’ which means ‘‘fish’’ in
English.1 Ichthyosis is appropriately named, given
that the skin of affected patients often resembles fish
scales. This category of diseases was first described in
1808 by Robert Wilan,2 a physician to the London
Dispensary.3 Ichthyosis was further studied and
expanded to include a number of distinct diseases
such as ichthyosis vulgaris, X-linked ichthyosis (XLI),
lamellar ichthyosis, and epidermolytic hyperkerato-
sis. XLI specifically was first recognized by Wells and
Kerr4 in 1965.
EPIDEMIOLOGY AND ORIGIN
XLI is a hereditary disorder of cutaneous keratin-
ization, with possible extracutaneous manifestations,
inherited in an X-linked recessive fashion. It is the
second most common type of ichthyosis, with a
prevalence of 1 in 6000, affecting almost exclusively
From Dermatology,a Pediatrics,b and Pathology,c New Jersey
Medical School.
Funding sources: None.
Conflicts of interest: None declared.
Reprint requests: Robert A. Schwartz, MD, MPH, Dermatology, New
Jersey Medical School, 185 South Orange Ave, Newark, NJ
07103. E-mail: roschwar@cal.berkeley.edu.
Published online January 18, 2010.
0190-9622/$36.00
ª 2009 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2009.04.028
gous women who were offspring of an affected man
and a female carrier.6,7 There is no noticeable racial
or geographic predilection.8
XLI is most commonly caused by a genetic defect
leading to a deficiency of the enzyme steroid sulfa-
tase (STS), also known as arylsulfatase C.9-11 A small
number of cases may be the consequence of other
genetic alterations of the X chromosome not directly
linked to the Sts gene.12 The gene coding for STS has
been mapped to the short arm of the X chromosome
at Xp22.3.13,14 This region of the X chromosome
escapes normal inactivation, so female carriers can-
not develop XLI through functional mosaicism.15
Approximately 80% to 90% of cases of XLI are a result
of complete deletions of the 146-kilobase gene.16
STS catalyzes the hydrolysis of aryl and alkyl steroid
sulfates such as dehydroepiandrosterone sulfate,
cholesterol sulfate, pregnenolone sulfate, and an-
drostenediol-3-sulfate to produce biologically active
steroids.16,17 Beyond the skin, STS has a wide variety
of physiologic functions in the breast, immune sys-
tem, brain, reproductive tract, osteoblasts, leuko-
cytes, and thrombocytes.16
PATHOPHYSIOLOGY
STS is normally found within the epidermis and is
thought to play a role in active cutaneous steroid
production and lipid regulation.16 Lipids normally
make up 11% of the epidermis; 10% of these lipids
are sterols such as cholesterol sulfate, which is the

480
J AM ACAD DERMATOL Fernandes, Janniger, and Schwartz 481
VOLUME 62, NUMBER 3

substrate for STS.8,18 Physiologic breakdown of
cholesterol sulfate leads to corneodesmosome deg-
19
radation and normal desquamation. A deficiency
of STS results in the accumulation of cholesterol
sulfate in the membranes of stratum corneum cells.20
Cholesterol sulfate is thought to play a role in
membrane integrity and normal desquamation
within the stratum corneum.
Therefore, a pathological in-
crease in quantity of choles- CAPSULE SUMMARY
terol sulfate results in
X-linked ichthyosis is an X-linked
d
XLI, normally appearing during adolescence or early
adulthood.8 These asymptomatic fine, flourlike
opacities can be seen in between 10% to 50% of
patients diffusely deposited in the posterior corneal
stroma or Descemet membrane.29-31 These corneal
opacities may present in 25% of female carriers as,
interestingly enough, the only finding related to
XLI.30 Although they almost
never affect visual acuity in
and of themselves, they may
lead to recurrent corneal
erosions.26

increased intracellular stabil-

18 recessive disorder of keratinization
ity and cohesion. The end Cryptorchidism is another
caused by a deficiency in steroid
result is partial retention extracutaneous finding, oc-
sulfatase activity.
hyperkeratosis with a pheno- curring in approximately
21
type of excess scaling. d Mild scaling in the first few days of life 20% of those with XLI.32
evolves to prominent brownish, There is also an increased
CLINICAL FEATURES polygonal, firmly adherent scales. risk of testicular germ cell
The first manifestation of d Corneal opacities, cryptorchidism, and cancer with XLI, which is
XLI may be delayed or pro- other abnormalities may be evident. independent of testicular
longed labor in mothers of maldescent.33,34 It is unclear
d
Diagnosis is clinical and is confirmed by
affected fetuses as a result of whether the increased risk of
biochemical or genetic analysis.
the absence of STS in the fetal cryptorchidism in XLI is
placenta, leading to de- caused by the deficiency of
creased levels of estrogen and insufficient dilation STS or concurrent mutations in nearby genes of the X
of the cervix.22,23 XLI, however, is not usually chromosome involved in testicular descent.35
detected until the first few weeks of life when However, patients have been shown to have normal
polygonal, loosely adherent translucent scales begin testosterone levels, sexual development, and
to appear in a generalized distribution and desqua- fertility.11
24
mate widely. They quickly develop into large, dark Neurologic findings may also be found in patients
brown, tightly adherent scales occurring primarily on with XLI, often occurring as manifestations of con-
the extensor surfaces and the side of the trunk tiguous gene syndromes. These abnormalities in-
symmetrically (Figs 1 and 2). These scales are often clude epilepsy with electroencephalographic
noted by the casual observer to look similar to the findings, mental retardation, and hyposmia.36 Other
scales of a fish and to have a ‘‘dirty’’ appearance. general alterations have rarely been described in
Initially the skin on the scalp, preauricular surfaces, patients with XLI. These findings include pyloric
and neck is almost always affected, but scales in this hypertrophy, congenital defect of the abdominal
distribution tend to largely disappear throughout wall, acute lymphoblastic leukemia, bilateral peri-
childhood.8 Consequently lower extremity altera- ventricular nodular heterotopia, and end-stage renal
tions tend to be more prominent in patients after failure.36-39 Contiguous gene involvement in patients
early childhood. Flexural surfaces are often affected, with XLI can result in a variety of syndromes includ-
whereas the palms, soles, hair, and nails are usually ing Rud syndrome, Conradi syndrome, and
spared.8 Patients with XLI also have decreased Kallmann syndrome.36 Patients with Rud syndrome
numbers of sweat glands and, hence, a reduction exhibit cryptorchidism, retinitis pigmentosa, mental
in sweat production.25 retardation, and epilepsy.40 Shortening of the limbs,
Extracutaneous findings are common in patients epiphyseal stippling, craniofacial defects, short stat-
with XLI as well (Table I). Ocular abnormalities are ure, and chondrodysplasia punctata are all features
seen frequently in the ichthyoses in general. These of Conradi syndrome.41 Kallmann syndrome is hy-
include asymptomatic irregularities of the eyelids, pogonadotropic hypogonadism with associated
conjunctiva, cornea, lens, and fundus.26 Ocular anosmia.
findings may occur in isolation or as part of
ichthyosis-related syndromes such as keratitis-ich- DIAGNOSIS
thyosis-deafness syndrome and ichthyosis-follicula- The diagnosis of XLI may be suggested during the
ris-alopecia-photophobia syndrome.27,28 Corneal prenatal course after a careful family history. History
opacities are the most common alteration seen in of a skin disease with significant scaling present in
482 Fernandes, Janniger, and Schwartz
Fig 1. Patient with X-linked ichthyosis with characteristic
large, dark brown, tightly adherent scales across his entire
back.
Fig 2. Patient with X-linked ichthyosis with characteristic
large, dark brown, tightly adherent scales along extensor
surfaces of his upper extremities.
only the male relatives of the mother should arouse
suspicion. If low to absent levels of estriol are
detected during the triple screen for alpha fetopro-
tein, human chorionic gonadotropin, and estriol
during the second trimester, this should alert the
physician to the possibility of XLI in the fetus.42
A birth history involving a prolonged or complicated
labor provides pertinent information as well. After
birth, a complete history and physical examination
aids largely in the identification of XLI. The time
course of the presentation is important, remember-
ing that 3 of 4 patients experience scaling by 1 week
of life.21 Drawing the family pedigree may elucidate
the mode of inheritance. Special attention should be
J AM ACAD DERMATOL
MARCH 2010
Table I. Extracutaneous manifestations of X-linked
ichthyosis
Ocular Corneal opacities (10%-50%)
Genitourinary Cryptorchidism (20%),
germ cell testicular cancer
Orthopedic Chondrodysplasia punctata
Neurologic Mental retardation, epilepsy
paid to the distribution, quality, and quantity of any
scaling.22 An eye examination demonstrating
comma-shaped opacities of the posterior capsule
can also be quite useful in terms of supporting the
correct diagnosis.22
The diagnosis of XLI may be confirmed through
biochemical or genetic analysis. Prenatal identifica-
tion can be made by detecting decreased estrogen
levels and the presence of nonhydrolyzed sulfated
steroids in maternal urine.38 If the genetic defect of
the Sts gene in the family is known, Southern blot,
fluorescent in situ hybridization, or polymerase
chain reaction can be performed on chorionic villi
or amniotic fluid samples.43 The diagnosis of XLI is
usually confirmed biochemically or genetically after
birth, however. Serum protein electrophoresis may
be performed to show increased mobility of the beta-
lipoprotein fraction as a result of elevated serum
cholesterol sulfate levels.21 Direct biochemical tech-
niques can be used to demonstrate deficiency of STS
activity in skin fibroblasts, leukocytes, and keratino-
cytes.8 Southern blot, fluorescent in situ hybridiza-
tion, and polymerase chain reaction are current
methods for confirming a causative mutation for
XLI. Sts gene deletions can be identified through
these techniques, but the few cases caused by point
mutations instead of deletions can be missed.44-46
Skin biopsy for histopathology is generally not
useful in confirming a diagnosis of XLI because
microscopic changes are often subtle and nonspe-
cific. Affected skin may appear normal or resemble
skin affected by ichthyosis vulgaris.21 One sees
hyperkeratosis with varying degrees of hypergranu-
losis in the epidermis (Fig 3).22 The dermis usually
exhibits edema with mild perivascular inflammation.8
However, a biopsy specimen may be beneficial in
considering other conditions with specific histopath-
ologic features in the differential diagnosis of XLI.
DIFFERENTIAL DIAGNOSIS
XLI may require distinction from atopic derma-
titis and other ichthyoses, most notably ichthyosis
vulgaris and lamellar ichthyosis. Ichthyosis vulgaris
is the most difficult to differentiate from XLI, and
can be hereditary or acquired.47 Ichthyosis vulgaris
J AM ACAD DERMATOL
VOLUME 62, NUMBER 3
Fig 3. Histopathological picture of X-linked ichthyosis
exhibiting subtle hyperkeratosis and hypergranulosis with
mild dermal perivascular inflammation (Hematoxylin-
eosin stain; original magnification: 3100.)
is associated with follicular keratosis and symmet-
ric, light gray scaling that appears after 3 months of
life.1 Flexural surfaces are usually spared, as op-
posed to XLI, in which flexural surfaces are often
affected.8 The histopathology of ichthyosis vulgaris
may appear similar to that of XLI. Biopsy specimen
generally shows basket-weave hyperkeratosis in the
stratum corneum, patchy parakeratosis, a markedly
decreased granular cell layer, and perivascular
lymphohistiocytic infiltration of the dermis.1
Hereditary ichthyosis vulgaris can be differentiated
from XLI because it is inherited in an autosomal-
dominant manner. Acquired ichthyosis, on the
other hand, is found almost exclusively in adults
and is considered a marker for cancer, infection, or
other serious systemic illnesses.48 Despite clinical
similarities between the two, XLI can ultimately be
differentiated from ichthyosis vulgaris, and other
cutaneous diseases, by demonstrating a deficiency
of STS.
MANAGEMENT
XLI is an incurable lifelong condition that rarely
affects normal life functions.49 Most patients with XLI
have disease limited to the skin. The majority of cases
improve with age and do not require treatment.8
Cutaneous symptoms are naturally alleviated during
summer months as well. However, some patients
with XLI and other types of ichthyoses experience a
significantly reduced quality of life. A 2004 Swedish
study showed that patients with XLI have a lower
health-related quality of life as evidenced by their
responses to the Dermatology Life Quality Index and
Standard Form 36 questionnaires.50 Therefore, life-
style modifications and pharmacologic therapies
Fernandes, Janniger, and Schwartz 483
should be prescribed when indicated to modulate
the abnormal keratinization by aiding in the shed-
ding of excess scale and blocking excessive
keratinization.8
Once the disease is recognized, one should initi-
ate topical therapy: cutaneous hydration, lubrication,
and keratolysis.22 One option for treatment of XLI is
to wear a plastic pajama suit overnight after applying
40% to 60% propylene glycol in water to the entire
body every night until excess scales are eliminated.51
Therapy then can be gradually weaned until once-a-
week use of the suit maintains clear skin.51 If the
patient is unable to tolerate this therapy, other
measures can be taken to focus on hydration.
Humidifying the home, school, and other environ-
ments during cold winter months often proves ben-
eficial.22 Bathing etiquette is important as well.
Soaking for prolonged periods and mechanical de-
bridement with a roughly textured sponge should be
encouraged, and lubricating bath oils followed by
application of creams and ointments after the bath,
while the skin is still wet, is useful.22
Topical keratolytics should be used as well.
Formulations that include lactic acid, glycolic acid,
salicylic acid in concentrations of 0.5% to 60%, and
urea in concentrations of 5% to 10% may be used.22
Goldsmith and Baden52 reported uniformly excellent
results after treating 10 patients with XLI with propy-
lene glycol in aqueous concentrations of 40% to 60%.
Lykkesfeldt and Høyer53 showed a good response to
10% cholesterol cream in 18 of 20 patients with XLI
treated and demonstrated that it was superior to urea
cream in most cases. Combination therapy with an
alpha-hydroxy acid and cholesterol cream may be an
excellent option.54 In neonates and infants, however,
topical keratolytics should be used with considerable
caution because their immature skin barrier function
and increased body surface area to weight ratio may
lead to increased percutaneous absorption and sys-
temic toxicity.55
Retinoic acid derivatives such as topical isotreti-
noin have also been shown to have considerable
success in treating patients with XLI.56,57 Frost and
Weinstein,58 in an early study, demonstrated a better
response in 6 of 8 patients with XLI treated with
vitamin-A acid versus placebo. A short-term paired
comparison on two patients with XLI suggested 0.1%
tretinoin cream was superior to 0.1% topical tretinoin
cream.59 Hofmann et al60 recently demonstrated
superior efficacy of the receptor-selective retinoid
tazarotene at 0.05% concentration in the treatment of
4 patients with XLI. Systemic absorption of this agent
when used topically for ichthyoses has since been
shown to be minimal.61 Although it has not been
effectively implemented as of yet, research is
484 Fernandes, Janniger, and Schwartz
underway regarding the possibility of using gene
transfer to treat XLI.62,63
Collaboration with other specialists may be help-
ful in successfully treating patients with XLI. Patients
and their families should be referred for genetic
counseling to receive further education regarding
XLI and its inheritance pattern. Potential risk in future
pregnancies should be emphasized as well, and the
obstetrician should be involved in this aspect of
management. In addition, patients should be advised
to perform regular testicular self-examinations, given
the increased risk of testicular germ cell cancer in
XLI. Physicians should also consider including
testicular evaluation as part of the physical exami-
nation of these patients.
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